Aberrant methylation of miR-124 upregulates DNMT3B in colorectal cancer to accelerate invasion and migration.

The dysregulation of microRNA expression is significantly associated with the initiation and development of CRC. miR-124 is markedly downregulated in colorectal cancer. In the present study, the effects of methylation, over expression and downregulation of miR-124 and its target gene DNMT3B on the proliferation, migration and invasion of colorectal cell line were investigated. The promoter methylation status of miR-124 in the CRC was investigated by methylation specific PCR (MSP). The potential role of miR-124 expression in CRC cells was investigated using the demethylation reagent 5-Aza-CdR and transfection of miR-124 mimic/antimir. MSP revealed that miR-124 promoter region was hypermethylated, result in its significant downregulation in tumour tissues. We showed miR-124 expression was upregulated following 5-AZA-CdR treatment. Transfected Hct-116 cell line with miR-124 leads to decreased DNMT3B expression, cell proliferation, migration and invasion of HCT-116. In conclusion, our data indicate that miR-124 suppress colorectal cancer proliferation, migration and invasion through downregulating DNMT3B level.

Recent Advances in siRNA Delivery Systems for Prostate Cancer Therapy.

The critical problems of conventional prostate cancer therapeutic strategies like nonspecific toxicity and multi-drug resistance prompted the development and application of countless nanoparticle- based siRNA therapeutics. Unfortunately, siRNA-based therapeutics suffer from the lack of safe and effective delivery systems, immune system stimulation, poor knowledge of nano-bio interactions, and limitations concerning designing, manufacturing, clinical translation, and commercialization. In this review, we provide cutting-edge advances in nanoparticle-mediated siRNA delivery carriers like polymeric systems, lipid systems, specific systems, and rigid nanoparticles for the treatment of prostate cancer. Moreover, co-delivery of conventional chemotherapy drugs with siRNA as a revolutionary robust strategy for prostate cancer combinational therapy is completely covered.

Hypermethylated miR-424 in Colorectal Cancer Subsequently Upregulates VEGF.

PURPOSE: Colorectal cancer (CRC) is the second leading cause of death from cancer in adults. Recent advances have shown that cancer cells can have some epigenetic changes involved in all stages of cancer. It has also been shown that miR-424 acts as gene expression regulators in many biological processes, including angiogenesis with mediators such as VEGF. In the current study, to identify the potential role of miR-424 in colorectal cancer progression, methylation status of miR-424 promoter region and its expression level have been evaluated. Besides, the correlation between VEGF level and miR-424 expression level has been assessed. METHODS: Methylation status miR-424 promoter was assessed using methylation-specific polymerase chain reaction (MSP). The expression level of miR-424 in human colorectal cancer tissue was analyzed by quantitative PCR. HCT116 cell line was selected to evaluate the correlation between the miR-424 expression level and the promoter's methylation status. VEGF expression, one out of mir-424 targets involved in angiogenesis and cancer progression, was measured by western blot analysis in the pairs of cancer tissues and their adjacent tissues. RESULTS: Our results have revealed that the promoter region of miR-424 is methylated in cancer cells compared to normal cells, leading to downregulation of miR-424 in the colorectal cancer tissues compared to the normal tissues. Also, we found that the expression protein's level of VEGF in the tumor cells is increased compared with normal tissues. CONCLUSION: The present study suggests that hypermethylation downregulates miR-424. VEGF expression is upregulated with decreased miR-424 in colorectal cancer, which results in cancer progression.

Therapeutic Attributes of Endocannabinoid System against Neuro-Inflammatory Autoimmune Disorders.

In humans, various sites like cannabinoid receptors (CBR) having a binding affinity with cannabinoids are distributed on the surface of different cell types, where endocannabinoids (ECs) and derivatives of fatty acid can bind. The binding of these substance(s) triggers the activation of specific receptors required for various physiological functions, including pain sensation, memory, and appetite. The ECs and CBR perform multiple functions via the cannabinoid receptor 1 (CB1); cannabinoid receptor 2 (CB2), having a key effect in restraining neurotransmitters and the arrangement of cytokines. The role of cannabinoids in the immune system is illustrated because of their immunosuppressive characteristics. These characteristics include inhibition of leucocyte proliferation, T cells apoptosis, and induction of macrophages along with reduced pro-inflammatory cytokines secretion. The review seeks to discuss the functional relationship between the endocannabinoid system (ECS) and anti-tumor characteristics of cannabinoids in various cancers. The therapeutic potential of cannabinoids for cancer-both in vivo and in vitro clinical trials-has also been highlighted and reported to be effective in mice models in arthritis for the inflammation reduction, neuropathic pain, positive effect in multiple sclerosis and type-1 diabetes mellitus, and found beneficial for treating in various cancers. In human models, such studies are limited; thereby, further research is indispensable in this field to get a conclusive outcome. Therefore, in autoimmune disorders, therapeutic cannabinoids can serve as promising immunosuppressive and anti-fibrotic agents.

Various interferon (IFN)-inducible transmembrane (IFITM) proteins for COVID-19, is there a role for the combination of mycophenolic acid and interferon?

Various interferon (IFN)-inducible transmembrane (IFITM) proteins are known to be expressed in human tissues though only IFITM 1-3 are inducible by IFN. Numerous studies have shown that activation of IFITM3 could suppress infection by influenza and coronaviruses such as the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). In view of the potential application of IFITM proteins' induction to target SARS-CoV-2 infection that causes COVID-19, this article layout insights into the known antiviral mechanisms and therapeutic agents related to IFITM. Blocking viral entry through various mechanisms and the potential application of the FDA approved immunosuppressant agent, mycophenolic acid, as inducer of IFITM3 are among those discussed.

Hesperetin is a potent bioactivator that activates SIRT1-AMPK signaling pathway in HepG2 cells.

Sirtuin 1 (SIRT1) is a deacetylase enzyme that plays crucial roles in controlling many cellular processes and its downregulation has been implicated in different metabolic disorders. Recently, several polyphenols have been considered as the effective therapeutic approaches that appear to influence SIRT1. The main goal of this study was to evaluate the effect of hesperetin, a citrus polyphenolic flavonoid, on SIRT1 and AMP-activated kinase (AMPK). HepG2 cells were treated with hesperetin in the presence or absence of EX-527, a SIRT1 specific inhibitor, for 24 h. Resveratrol was used as a positive control. SIRT1 gene expression, protein level, and activity were measured by RT-PCR, Western blotting, and fluorometric assay, respectively. AMPK phosphorylation was also determined by Western blotting. Our results indicated a significant increase in SIRT1 protein level and activity as well as an induction of AMPK phosphorylation by hesperetin. These effects of hesperetin were abolished by EX-527. Furthermore, hesperetin reversed the EX-527 inhibitory effects on SIRT1 protein expression and AMPK phosphorylation. These findings suggest that hesperetin can be a novel SIRT1 activator, even stronger than resveratrol. Therefore, the current study may introduce hesperetin as a new strategy aimed at upregulation SIRT1-AMPK pathway resulting in various cellular processes regulation.

Association between activity and genotypes of paraoxonase1 L55M (rs854560) increases the disease activity of rheumatoid arthritis through oxidative stress.

Rheumatoid arthritis (RA) is considered as a long-term autoimmune disorder. Gene polymorphism and oxidative stress might be involved in the pathogenesis of the disease. We aimed to determine the association between PON-1L55M polymorphism and its effects on inflammatory markers such as anti-cytroline circulated-peptide (CCP)-antibodies, C-reactive protein (CRP), neopterin serum concentration, arylesterase (ARE) and butyrylcholinesterase (BuChE) activities and total-antioxidant-capacity (TAC) level with the activity of disease in RA patients. This case-control study consisted of 419 RA patients and 397 gender-age-matched unrelated healthy controls from the west of Iran. PON1-L55M polymorphism was detected by real-time-PCR. The TAC level, serum BuChE and ARE activities were determined spectrophotometrically. Anti-CCP-antibody and CRP were measured by ELISA and neopterin level was detected by HPLC. The PON1-M55 allele was associated with increased risk of the RA in cases with moderate or high activity (OR = 1.43, p = 0.023) and also in cases with the presence of anti-CCP antibody (OR = 1.51, p = 0.009). Synergistic effects of PON1 M55 and Q192 alleles resulted in 2.14 times (p = 0.021) increased disease activity among RA patients with moderate or high activity of the disease. RA patients carried both M (PON1 L55M) and Q alleles (PON1Q192R) had higher concentrations of neopterin (p = 0.003), anti-CCP-antibody (p < 0.001) and CRP (p = 0.026) and significantly lower TAC level (p < 0.001) and ARE (p < 0.001) activity compared to controls. The current study suggests there might be a relationship between genetic and activity of PON. Also, the PON1L55M and PON1Q192R could act in synergy to increase the risk of RA and enhance the level of oxidative stress markers.

Decreased serum levels of CTRP12/adipolin in patients with coronary artery disease in relation to inflammatory cytokines and insulin resistance.

Coronary artery disease (CAD) is the leading cause of death worldwide. Atherosclerosis as the main underlying mechanism of CAD is associated with inflammation and adipose tissue dysfunction. C1q/TNF-related protein12 (CTRP12) is a newly discovered adipokine which is a paralog of adiponectin. CTRP12 has anti-inflammatory and insulin sensitizing effects. Circulating levels of this adipokine have been reported to be lower in patients with type 2 diabetes and women with polycystic ovarian syndrome. The present study was undertaken for the first time to evaluate serum levels of CTRP12 in CAD patients and its association with anthropometric and biochemical parameters. Serum levels of CTRP12 were measured using ELISA kit in 188 CAD patients (angiography confirmed) and 70 controls. The serum levels of adiponectin, TNF-α and IL-6 were measured using ELISA kits. Serum levels of CTRP12 were found to be lower in CAD patients (585.48 ±â€¯201.67 pg/mL) than in the controls (814.86 ±â€¯247.85 pg/mL; p < 0.001). CTRP12 also showed an independent association with the risk of CAD (OR [CI] = 0.998 [0.996-0.999]; p = 0.019). Moreover, it showed an inverse correlation with HOMA-IR (r = -0.298; p = 0.012) and TNF-α (r = -0.269; p = 0.023) and a positive correlation with adiponectin (r = 0.344; p = 0.003) in the controls. In CAD patients, CTRP12 was inversely correlated with BMI (r = -0.181, p = 0.013), HOMA-IR (r = -0.199; p = 0.006), TNF-α (r = -0.259; p < 0.001) and IL-6 (r = -320; p < 0.001) and a positive correlation with high density lipoprotein-cholesterol(r = 0.342; p < 0.001) and adiponectin (r = 0.398; p < 0.001). The present study showed for the first time that serum levels of CTRP12 are independently associated with CAD and that CTRP12 is associated with several CAD risk factors. The results suggest a possible link between CTRP12 and pathogenic mechanisms of atherosclerosis, such as inflammation and high density lipoprotein-cholesterol metabolism; however, more study is required in this regard.

Investigating the effect of visfatin on ERalpha phosphorylation (Ser118 and Ser167) and ERE-dependent transcriptional activity.

Obesity is associated with higher postmenopausal breast cancer incidence. Visfatin level alteration is one of the mechanisms by which obesity promotes cancer. Ligand-independent activation of estrogen receptor alpha (ERα) is also associated with carcinogenesis. The activity of ERα is modulated through phosphorylation on multiple sites by a number of protein kinases. Here we investigated the effect of visfatin as a novel adipocytokine on the phosphorylation and activity of ERα in MCF-7 breast cancer cells. We showed that exogenous administration of visfatin significantly increased the phosphorylation of ERα at serine 118 (Ser118) and 167 (Ser167) residues. Visfatin-induced Ser118 phosphorylation was diminished after treatment of cells with U0126 (MEK1/2 inhibitor). Furthermore, our results showed that visfatin-induced Ser167 phosphorylation is mediated through both MAPK and PI3K/Akt signaling pathways. Inhibition of the enzymatic activity of visfatin by FK866 had no effect on phosphorylation of ERα. We also showed that visfatin enhanced the estrogen response element (ERE)-dependent activity of ER in the presence of 17-ß estradiol (E2). Additional study on T47D cells showed that visfatin also increased Ser118 and Ser167 phosphorylation of ERα and enhanced ERE-dependent activity in the presence of E2 in these cells.

Association between butyrylcholinesterase activity and phenotypes, paraoxonase192 rs662 gene polymorphism and their enzymatic activity with severity of rheumatoid arthritis: correlation with systemic inflammatory markers and oxidative stress, preliminary report.

OBJECTIVES: Evidences indicate that oxidative stress and inflammation are important processes in the development of destructive synovial tissue in rheumatoid arthritis (RA). The two major bioscavenger enzymes that are associated with inflammation and oxidative stress are human-butyrylcholinesterase (BuChE) and paraoxonase-1 (PON-1). Thus, the objective of this study was to determine the relation of BuChE phenotypes and PON-1 Q192R polymorphism with inflammatory markers such as anti-cytroline circulated peptide (CCP)-antibodies, CRP, neopterin, DAS28-CRP in RA patients. DESIGN AND METHODS: In this study, we examined association of BuChE-phenotypes and activity, PON192rs662 (Q192R) polymorphism and its arylesterase activity (ARE) with systemic-inflammatory-markers and oxidative stress. The present case-control study consisted of 419-RA patients and 398 gender-age-matched unrelated healthy controls from west population of Iran. PON192rs662 polymorphism was detected by real-time-PCR. BuChE phenotype, TAC level, serum BuChE and ARE activities were determined spectrophotometrically. Anti-CCP-antibody and CRP were measured by ELISA and neopterin level was detected by HPLC. We used the EULAR activity criteria to measure DAS28-CRP. RESULTS: We found that PON-1-Q192R was associated with severity of RA [remission-to-low and moderate-to-high in dominant Q/Q+Q/R vs. R/R: OR=2.27, p<0.001; codominant Q/Q vs. R/R: OR=1.65, p<0.001 and Q/R vs. R/R: OR=2.12, p=0.003; recessive Q/Q vs. R/R+Q/R: OR=1.79, p=0.032; and allele Q vs. R: OR=1.68, p<0.001] and presence of anti-CCP-antibody (codominant model Q/Q vs. R/R: OR=1.28, p=0.042). The carriers of Q/Q genotype PON-1-Q192R and BuChE non-UU-phenotype had higher ARE activity, serum levels of neopterin, anti-CCP antibody titer and number of tender-joint and lower activity of BuChE and serum level of TAC than that of R/R genotype and BuChE-UU-phenotype. CONCLUSIONS: The current findings demonstrate for the first time that there is a link between systemic inflammatory markers, oxidative stress, the PON192rs662-Q allele and BuChE-non-UU-phenotype and their corresponding enzymatic activity which may be considered as a risk factor for the severity of RA for a population in Iran.